Angiotensin Receptor Blockade by Inhibiting Glial Activation Promotes Hippocampal Neurogenesis Via Activation of Wnt/β-Catenin Signaling in Hypertension

Abstract

Hypertension is one of the major risk factors for central nervous system (CNS) disorders like stroke and Alzheimer’s disease (AD). On the other hand, CNS diseases like AD have been associated with gliosis and impaired neurogenesis. Further, renin angiotensin system (RAS) is intricately associated with hypertension; however, the accumulating evidences suggest that over-activity of RAS may perpetuate the brain inflammation related with AD. Therefore, in the present study, we examined the effect of hypertension and RAS on glial (astrocytes and microglia) activation and hippocampal neurogenesis in a rat model of chronic hypertension. We used Candesartan [angiotensin type 1 receptor (AT1R) blocker (ARB)] both at a low dose (0.1 mg/kg) and anti-hypertensive dose (2 mg/kg) to explore whether their effect on astrocyte and microglial activation, neuroinflammation, and neurogenesis is blood pressure (BP) dependent or independent. Our data revealed that hypertension induces robust microglial and astrocyte activation, neuroinflammation, and cripples hippocampal neurogenesis. Importantly, AT1R blockade by Candesartan, even at low dose (0.1 mg/kg), prevented astrocyte and microglial activation and neuroinflammation in the brain of hypertensive rats. Mechanistically, AT1R blockade prevented the activation of NADPH oxidase, reactive oxygen species (ROS) generation, suppression of MAP kinase and NFкB signaling. Importantly, we, for the first time to our knowledge, provided the evidence that AT1R blockade by activating Wnt/β-catenin signaling, promotes neurogenesis during hypertensive state. We conclude that AT1R blockade prevents astrocyte and microglial activation and improves hippocampal neurogenesis in hypertensive state, independent of BP lowering action.

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Acknowledgments

The authors are highly thankful to Mr. A. L. Vishwakarma, Mrs. M. Chaturvedi and Mr. Dhananjay Sharma for their help with the flow cytometry and confocal microscopy procedures, respectively. We are extremely thankful to Ms. Anika Sood and Ms. Zoya Fatima for quantification of immunohistochemical data in the study. We are highly thankful to Mr. Jitender Singh Kanshana and Mr. Anant Jaiswal for help in real-time PCR studies. We also acknowledge THUNDER (BSC0102) and MoES (GAP0118) for the confocal facility. The CSIR-CDRI Communication number of this article is 9554.

Funding

The study was supported by a financial grant to Kashif Hanif from Department of Biotechnology (DBT, grant No. BT/PR4021/MED/30/676/2011) and CSIR Network Project MIND (BSC0115). Award of research fellowships to SAB from Indian Council of Medical Research (ICMR), and RG from UGC, New Delhi, are greatly acknowledged.

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Correspondence to Kashif Hanif.

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Bhat, S.A., Goel, R., Shukla, S. et al. Angiotensin Receptor Blockade by Inhibiting Glial Activation Promotes Hippocampal Neurogenesis Via Activation of Wnt/β-Catenin Signaling in Hypertension. Mol Neurobiol 55, 5282–5298 (2018). https://doi.org/10.1007/s12035-017-0754-5

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Keywords

  • Hypertension
  • Glial activation
  • Neurogenesis
  • AT1R blockade
  • Neuroinflammation